Immunopharmacology Flashcards
Affects of cortisol
Increase?
Decrease?
Increases annexing 1 (inhibits PLA2 from making arachidonic acid), secretory leukoprotease inhibitor (SLPI), IL-10 (anti-inflammatory), NFkB inhibitor
Decreases COX-2, cytokines, chemokines, and CAMs
Prednisone Class Use Metabolism Mechanism Adverse rxns Precautions
Glucocorticoid
Immunosuppressive drug for autoimmune, allograft, asthma, IBD, RA. Prodrug, must be metabolized to prednisolone.
Mechanism – Acts on nuclear receptors → modulates gene expression. Inhibits COX-2 expression, decreases cytokines, induces apoptosis of eosinophils.
Adverse rxns: CNS, GI, cataracts, opportunistic infections
Precautions: Cushing’s, avoid abrupt DC of prolonged therapy due to suppression of HPA axis, preexisting infections, check for cataracts
Cyclosporine Class Use Mechanism What is Restasis used for? Adverse rxns Precautions
Signal transduction inhibitor
Prevents organ rejection. Tx RA, psoriasis, and IBD.
Mechanism – Calcineurin inhibitor (CNI) – binds to cyclophilin, complex binds to calcineurin to inhibit phosphatase activity of calcineurin. Prevents dephosphorlation / translocation of NF-AT (transcription factor) from stimulating cytokine expression. Inhibits T cell activation, IL-2, 3, 4, TNFa, and IFNg.
Restasis is drug used to increase tear production after inflammation.
Adverse rxns: nephrotoxicity (main side effect, fibrosis and vasoconstriction of afferent arterioles), HTN, hirsutism, gingival hyperplasia
Precuations: therapeutic drug monitoring (keep trough level at 150-200 ng / mL), hepatic / renal disease, HTN
Tacrolimus Class Use Mechanism Metabolism What organ is it concentrated in? Adverse rxns Precautions
Signal transduction inhibitor
Prevents organ rejection. Tx psoriasis and atopic dermatitis.
Mechanism – CNI (but diff than cyclosporine): forms complex w/ FK binding protein, which binds calcineurin to inhibit phosphatase activity, which prevents dephosphorylation / translocation of NF-AT. 50-100x more potent than cyclosporine.
Metabolized by CYP3A4 (drug interactions)
Concentrated in pancreas. May inhibit pancreatic insulin secretion.
Adverse rxns: nephrotoxicity, HTN, CNS (tremor, insomnia, headache all common), GI (NVD, elevated LFTs), hyperglycemia (much higher than cyclosporine)
Precautions: diabetes (give cyclosporine instead), therapeutic drug monitor required (5-20 ng/ mL, smaller window)
Sirolimus Class Use Mechanism Metabolism Adverse rxns Precautions
Signal transduction inhibitor
Prevents kidney transplant rejection (not used for liver or lung)
•Mechanism – Not a CNI, but rather inhibits proliferation signal. Binds FK binding protein, complex binds / inhibits mTOR, which inhibits progression from G1 to S. Cytostatic (T cells still produce IL-2 but fail to proliferate)
•Metabolized by CYP3A4 (drug interactions). Toxic levels may be reached if administered w/ grapefruit juice or azoantifungals (inhibit CYP enzymes).
•Adverse rxns: dyspnea, pharyngitis, myelosuppresion (bone marrow), hyperlipidemia, hypertriglyceridemia, edema, may potentiate CNI-induced nephrotoxicity (don’t use together)
•Precautions – drug monitoring
Azathioprine Class Use Metabolism Mechanism Adverse rxns Precautions
Purine Synthesis Inhibitor
Prevents rejection after kidney transplant. Tx RA and Crohn’s disease.
•Prodrug of 6-mercaptopurine (6-MP), which can be used as antileukimia agent
•6-MP is inactivated by oxidation (via xanthine oxidase) and methylation (via thiopurine S-methyltransferase).
•Mechanism – Azathioprine → 6-MP → 6-thioguanine → 6-thioguanine nucleotides → incorporated into DNA and RNA → impaired function. 6-MP and 6-thioguanine also inhibit enzymes in nucleotide biosynthetic pathway → decreased purines / ATP.
•Adverse rxns: myelowsuppression (half of people) w/ possible leucopenia
•Precautions: allupurinol (enhanced toxicity, blocks xanthine oxidase), pregnancy D
Mycophenolate mofetil Class Use Mechanism Selective for which type of cells? Excretion Adverse rxns Precautions
Purine Synthesis Inhibitor
Prevent organ rejection after renal, cardiac, or liver transplant. Used concomitantly or as alternative to cyclosporine or tacrolimus. May add corticosteroid as well. Less bone marrow suppression than azathiprine.
•Mechanism – Prodrug of mycophenolic acid, which is a reversible inhibitor of inosine monophosphate dehydrogenase → inhibits guanosine biosynthesis (normally required for lymphocyte proliferation / activation) → blunted T and B cell response.
•Selective for lymphocytes b/c other cells are able to recover purines via salvage pathway
•Excreted entirely in urine
•Adverse rxns: HTN, myelosuppresion, acne / rash
•Precautions: renal insufficiency, pregnancy risk category D
Muromonab-CD3 Class Use Mechanism Adverse rxns Precautions
Immunosuppressive Antibody
Blocks acute rejection of heart, liver, and kidney transplants. Depletes T cells from donor bone marrow prior to transplantation. Taken for 1-2 weeks after transplant.
Mechanism – Murine (mouse) monoclonal Ab binds to T cell receptor-associated CD3 complex → blockade, apoptosis, and depletion of T cells.
Adverse rxns: triggers cytokine release syndrome (fever, chills, tx w/ acetaminophen)
Precautions: allergy to mouse proteins, CV
Basiliximab Class Use Use w/ which other drugs? Mechanism Adverse rxns Precaution
Immunosuppressive Antibody
Prevents acute rejection following kidney transplant. Combine w/ cyclosporine + glucocorticoid.
•Mechanism – Anti-CD25 Ab blocks IL-2 receptor on activated T cells.
•CD25 only expressed on activated T cells, so drug does not cause widespread depletion of T cells.
•Much lower adverse rxns than muromonoab: GI, CV
•Precaution: allergy to mouse proteins (due to recombinant human-mouse IgG)
Adalimumab Brand name Class Use Mechanism Precautions
Humira
Immunosuppressive Antibody
Tx RA, Crohn’s disease, ankylosing spondylitis, psoriasis.
Mechanism – Fully humanized Ab binds / blocks TNFa receptor → reduces pro-inflammatory cytokines (IL-1, 6), leukocyte migration, activation of neutrophils, eosinophils, fibroblasts, prostaglandins, MMPs (less cartilage breakdown)
Precautions: Chronic / recurrent infection, TB
Betalacept
Use
Mechanism
Immunosuppressant
Mimics CTLA4. B7 binds this instead of CD28 → prevents costimulation, T cell activation, cytokine production, and Ab production
